Sinomeni Caulis et Rhizoma refers to the dried stems and rhizomes of Sinomenium acutum (Thunb.) Rehder & E.H.Wilson (Menispermaceae). Traditionally, Sinomeni Caulis et Rhizoma has been used to treat conditions such as pain, inflammation, and arthralgia. Modern pharmacological studies have shown that it possesses anti-inflammatory, analgesic, and immunomodulatory effects. This study investigated the effects of Sinomeni Caulis et Rhizoma water extract (SCWE) on RANKL-induced osteoclast differentiation in Bone Marrow Macrophages (BMMs) and bone loss in an ovariectomized (OVX) animal model. SCWE significantly reduced the number of RANKL-induced TRAP-positive multinucleated cells (TRAP⁺MNCs) and inhibited the RANKL-mediated induction of c-Fos and nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 (NFATc1) in BMMs. It also inhibited the formation of F-actin rings during RANKL-mediated osteoclast differentiation. SCWE suppressed inhibited the expression of various osteoclast differentiation-associated genes, such as TRAP, ATPase H⁺ transporting lysosomal 38kDa V0 subunit d2 (ATP6V0D2), osteoclast-stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP), MMP-9, OSCAR, calcitonin receptor and cathepsin K. Consistent with our in vitro results, micro-CT analysis showed that SCWE prevented ovariectomy (OVX)-mediated bone loss. These results suggest that SCWE might help treat various bone-destructive diseases associated with excessive bone loss.